High Affinity Ligands Bind to Clostridium Difficile Toxin A

Abstract

Glycans are identified which have high affinity for C. difficile toxin A. They share one of two saccharide backbones and may have additional side chains. The backbones are galactose-β 1-3 N-acetyl-D-glucosamine-β-1-3-galactose-β-1-4-N-acetyl-D-glucosamine and galactose-α-1-3-galactose-β-1-4-N-acetyl-D-glucosamine. The ligands may be used therapeutically, prophylactically, and diagnostically.

1 . A method of treating a mammal to reduce symptoms or to delay onset of  Clostridium difficile  infection or to reduce or prevent  Clostridium difficile  mediated intestinal damage, comprising:
 administering to a mammal an oligosaccharide having a structure galactose-α-1-3-galactose-β-4-N-acetyl-D-glucosamine and comprising one or more side chains.   
     
     
         2 . The method of  claim 1  wherein the side chain is a fucose moiety. 
     
     
         3 . The method of  claim 1  wherein the side chain is an α2-linked fucose moiety. 
     
     
         4 . The method of  claim 1  wherein the side chain is an α3-linked fucose moiety. 
     
     
         5 . The method of  claim 1  wherein the oligosaccharide is covalently attached to a non-absorbable polymer. 
     
     
         6 . The method of  claim 1  wherein the mammal is a human. 
     
     
         7 . The method of  claim 1  wherein the mammal is a farm animal. 
     
     
         8 . The method of  claim 1  wherein the mammal is a companion animal. 
     
     
         9 . The method of  claim 1  wherein the mammal is infected with  C. difficile.    
     
     
         10 . The method of  claim 1  wherein the mammal is at risk of infection with  C. difficile.    
     
     
         11 . The method of  claim 1  wherein the agent is glycan no. 103. 
     
     
         12 . The method of  claim 6  wherein the human is hospitalized. 
     
     
         13 . The method of  claim 6  wherein the human is immunosuppressed. 
     
     
         14 . The method of  claim 6  wherein the human is a transplant recipient. 
     
     
         15 . The method of  claim 6  wherein the human is HIV positive. 
     
     
         16 . The method of  claim 6  wherein the human has been treated with clindamycin. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an agent comprising an oligosaccharide having a structure galactose-α-1-3-galactose-β-1-4-N-acetyl-D-glucosamine and comprising one or more side chains. 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the carrier is a liquid. 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein the carrier is a solid. 
     
     
         20 . The pharmaceutical composition of  claim 17  further comprising a non-absorbable polymer. 
     
     
         21 . The pharmaceutical composition of  claim 17  wherein the oligosaccharide is attached to the non-absorbable polymer. 
     
     
         22 . The pharmaceutical composition of  claim 17  wherein the agent is glycan no. 103. 
     
     
         23 . The pharmaceutical composition of  claim 17  further comprising an antibiotic to which  Clostridium difficile  is sensitive. 
     
     
         24 . The pharmaceutical composition of  claim 22  wherein the antibiotic is metronidazole. 
     
     
         25 . The pharmaceutical composition of  claim 22  wherein the antibiotic is vancomycin.